1. Field of the Invention
The present invention relates to a method for modulating inflammatory and pro-inflammatory states in a patient in need thereof by contacting the bodily fluid of the patient with renal tubule cells outside of the kidney.
2. Discussion of the Background
It is widely recognized that inflammatory cytokines play a role in the etiology of a variety of disease states, such as malnutrition, chronic congestive heart failure, inflammatory bowel disease, Crohn's disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, systemic vasculitis, lupus, Wegener's granulomatosis, polyarteritis nodosa, dermatomyositis, diabetes mellitus Type I, thyroiditis, psoriasis, Guillian Barre syndrome, multiple sclerosis, and atherosclerosis, or other autoimmune disorders. [Refs. 1, 20, 21, 22, 23, 24, 25, 31, 32, 33, 34, 35, 36, 37, 38, 39]. Modulating the levels of such cytokines may provide a method of treating such patients. Accordingly, there remains a critical need for novel inflammation modulatory therapies for the treatment of patients suffering from, for example, at least one of the diseases discussed above.
Although maintenance dialysis therapy for end-stage renal disease (ESRD) has been used for almost 40 years, annual mortality rates among patients with ESRD undergoing hemodialysis remain greater than 20%. [Refs. 1, 2]. The most common cause of death in end-stage in ESRD patients (about 50%) is of cardiac or cardiovascular origin, with infection/sepsis (about 15%) being second. [Ref. 1].
The mortality from sepsis complicated by renal failure remains extremely high despite the application of modern renal replacement therapy. The systemic inflammatory response syndrome, or SIRS, is a catastrophic sequela of a variety of clinical insults, including infection, pancreatitis and cardiopulmonary bypass, and claims over a quarter million lives in the United States each year. [Refs. 3, 4, 5, 6, 7, 8].
The mortality is especially high in patients with multiple system organ failure syndrome (MSOF) and acute renal failure (ARF). The excess mortality seen in patients with sepsis and ARF is not ameliorated by conventional renal replacement therapy, which treats volume overload, uremia, acidosis, and electrolyte derangements. [Refs. 9, 6].
The prevalence of inflammation is high in dialysis patients; several lines of evidence suggest the presence of an ongoing acute-phase reaction in patients with ESRD undergoing hemodialysis. [Refs. 10, 11, 12]. Blood monocytes from hemodialysis patients are primed for cytokine production and predialysis serum contains elevated concentrations of inflammatory cytokines (for example, tumor necrosis factor-alpha [TNF-α], interleukin-beta [IL-1β], interleukin-1, [IL-1], interleukin-6 [IL-6], interleukin-8 [IL-8], lipopolysaccharide biding protein, soluble lipopolysaccharide receptors [CD-14], GM-CSF, G-CSF, and chemokines) and anti-inflammatory cytokines (soluble TNF receptors [TNF-RI and TNF-RII], interleukin receptor antagonist [IL-1ra], interleukin-4 [IL-4], interleukin-10 [IL-10], interleukin-12 [IL-12], interleukin-13 [IL-13], and transforming growth factor-β [TGF-β]). [Refs. 13, 14, 15, 16, 17, 30].
In fact, one of the strongest independent risk factors of mortality among patients undergoing hemodialysis is hypoalbuminemia. [Refs. 18, 19]. The generation of albumin is reduced and hypoalbuminemia develops as part of the acute phase response, mediated by proinflammatory cytokines (most directly interleukin-6 [IL-6]). [Ref. 2]. Accordingly, there remains an ongoing need for new methods for modulating the inflammatory response among hemodialysis patients.